Detecting blocked arteries early using nanoparticles could save a LOT of lives

THE CHUNG LAB TEAM’S NANOPARTICLE MICELLES (LEFT) WITH FLUORESCENT TAGS, ATTACH THEMSELVES TO MICROCALCIFICATION IN ATHEROSCLEROSIS.

New nanotechnology will allow detection of blocked arteries more effectively than ever before

Heart disease and stroke are the world’s two most deadly diseases, causing over 15 million deaths in 2016 according to the World Health Organization. A key underlying factor in both of these global health crises is the common condition, atherosclerosis, or the build-up of fatty deposits, inflammation and plaque on the walls of blood vessels. By the age of 40, around half of us will have this condition, many without symptoms.

A new nanoparticle innovation from researchers in USC Viterbi’s Department of Biomedical Engineering may allow doctors to pinpoint when plaque becomes dangerous by detecting unstable calcifications that can trigger heart attacks and strokes.

The research ­­— from Ph.D. student Deborah Chin under the supervision of Eun Ji Chung, the Dr. Karl Jacob Jr. and Karl Jacob III Early-Career Chair, in collaboration with Gregory Magee, assistant professor of clinical surgery from Keck School of Medicine of USC — was recently published in the Royal Society of Chemistry’s Journal of Materials Chemistry B on 25 September 2019.

When atherosclerosis occurs in coronary arteries, blockages due to plaque or calcification-induced ruptures can lead to a clot, cutting blood flow to the heart, which is the cause of most heart attacks. When the condition occurs in the vessels leading to the brain, it can cause a stroke.

“An artery doesn’t need to be 80 percent blocked to be dangerous. An artery with 45% blockage by plaques could be more rupture-prone,” Chung said. “Just because it’s a big plaque doesn’t necessarily mean it’s an unstable plaque.”

Chung said that when small calcium deposits, called microcalcifications, form within arterial plaques, the plaque can become rupture prone.

However, identifying whether blood vessel calcification is unstable and likely to rupture is particularly difficult using traditional CT and MRI scanning methods, or angiography, which has other risks.

“Angiography requires the use of catheters that are invasive and have inherent risks of tissue damage,” said Chin, the lead author. “CT scans on the other hand, involve ionizing radiation which can cause other detrimental effects to tissue.”

Chung said that the resolution limitations of traditional imaging offers doctors a “bird’s eye view” of larger-sized calcification, which may not necessarily be dangerous. “If the calcification is on the micro scale, it can be harder to pick out,” she said.

The research team developed a nanoparticle, known as a micelle, which attaches itself and lights up calcification to make it easier for smaller blockages that are prone to rupture to be seen during imaging.

Chin said the micelles are able to specifically target hydroxyapatite, a unique form of calcium present in arteries and atherosclerotic plaques.

“Our micelle nanoparticles demonstrate minimal toxicity to cells and tissue and are highly specific to hydroxyapatite calcifications,” Chin said. “Thus, this minimizes the uncertainty in identifying harmful vascular calcifications.”

The team has tested their nanoparticle on calcified cells in a dish, within a mouse model of atherosclerosis, as well as using patient-derived artery samples provided by vascular surgeon, Magee, which shows their applicability not only in small animals but in human tissues.

“In our case, we demonstrated that our nanoparticle binds to calcification in the most commonly used mouse model for atherosclerosis and also works in calcified vascular tissue derived from patients,” Chin said.

Chung said that the next step for the team was to harness the micelle particles to be used in targeted drug therapy to treat calcification in arteries, rather than just as means of detecting the potential blockages.

“The idea behind nanoparticles and nanomedicine is that it can be a carrier like the Amazon carrier system, shuttling drugs right to a specific address or location in the body, and not to places that you don’t want it to go to,” Chung said.

“Hopefully that can allow for lower dosages, but high efficacy at the disease site without hurting normal cells and organ processes,” she said.

Learn more: Lighting Up Cardiovascular Problems Using Nanoparticles

 

 

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A promising therapeutic approach to halt and potentially reverse plaque buildup in arteries

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In a new Yale-led study, investigators have revealed previously unknown factors that contribute to the hardening of arteries and plaque growth, which cause heart disease. Their insight is the basis for a promising therapeutic approach to halt and potentially reverse plaque buildup and the progression of disease, the researchers said.

The study was published online by Nature Metabolism.

Current treatments for plaque and hardened arteries, a condition known as atherosclerosis, can slow but not improve the disease. Experts believe that may be due to ongoing inflammation in blood vessels. To understand the factors contributing to this inflammation, the research team focused on a group of proteins, called transforming growth factor beta (TGFß), that regulates a wide range of cells and tissues throughout the body.

Using cultured human cells, the researchers discovered that TGF? proteins trigger inflammation in endothelial cells — the cells that form the inner lining of artery walls — but not in other cell types. With a technique called single cell RNA-seq analysis, which measures the expression of every gene in single cells, they then showed that TGF? induced inflammation in these cells in mouse models. This finding was notable, said the researchers, because TGF? proteins are known to decrease inflammation in other cells in the body.

The researchers also showed that when the TGF? receptor gene is deleted in endothelial cells, both the inflammation and plaque in blood vessels are significantly reduced.

To test this approach as a potential therapy, the team, led by professor of medicine Michael Simons, M.D., used an “interfering” RNA, or RNAi, drug developed at Yale, to disrupt TGFß receptors. Interfering RNA use a gene’s own DNA sequence to turn off or silence the gene. To deliver the drug only to endothelial cells in the blood vessel walls of mice, they employed microscopic particles, or nanoparticles, created by their co-authors at MIT. This strategy reduced inflammation and plaque as effectively as the genetic technique.

The findings identify TGFß signaling as a major cause of chronic vessel wall inflammation, and demonstrate that disruption of this pathway leads to cessation of inflammation and substantial regression of existing plaque, said the scientists.

Based on this discovery, investigators at Yale and MIT have launched a biotech company, VasoRX, Inc., to develop this targeted approach, using the RNAi drug delivered by nanoparticles as a potential therapy for atherosclerosis in people.

Learn more: Yale-led study offers promising approach to reducing plaque in arteries

 

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A potential new approach for preventing or reversing a number of inflammatory diseases

The aorta of a mouse model of atherosclerosis on a high-fat diet for 12 months (top) has significantly more plaques (bright red) than the aorta of the same type of mouse that also produces the anti-inflammatory E06 antibody (bottom).

Study uncovers new potential therapeutic approach for a number of diseases linked to inflammation, including atherosclerosis, aortic stenosis and hepatic steatosis

Researchers at University of California San Diego School of Medicine discovered that they can block inflammation in mice with a naturally occurring antibody that binds oxidized phospholipids (OxPL), molecules on cell surfaces that get modified by inflammation. Even while on a high-fat diet, the antibody protected the mice from arterial plaque formation, hardening of the arteries and liver disease, and prolonged their lives.

This study, published June 6 by Nature, marks the first demonstration in a living system that OxPL triggers inflammation and leads to plaque formation. The results also suggest a new approach for preventing or reversing a number of inflammatory diseases.

“Wherever you get inflammation, you get OxPL,” said senior author Joseph Witztum, MD, professor of medicine at UC San Diego School of Medicine. “It doesn’t mean OxPL is the cause, but it definitely plays a major role.” Witztum led the study with first author Xuchu Que, PhD, a senior project scientist at UC San Diego School of Medicine.

Some phospholipids — the molecules that make up cell membranes — are prone to modification by reactive oxygen species, forming OxPL. This event is particularly common in inflammatory conditions such as atherosclerosis, in which artery-blocking plaques form. Prior to this study, researchers were unable to control phospholipid oxidation in a way that would allow them to study its role in inflammation and atherosclerosis.

Witztum, Que and team engineered mice with two special attributes: 1) they have a gene mutation that makes them a good model for atherosclerosis and 2) they generate a piece of an antibody called E06 that’s just enough to bind OxPL and prevent their ability to cause inflammation in immune cells, but not enough to cause inflammation on its own. They fed the mice a high-fat diet.

Here’s what happened: Compared to control mice, the mice with E06 antibodies had 28 to 57 percent less atherosclerosis, even after one year and despite having high levels of cholesterol. The antibody also decreased aortic valve calcification (hardening and narrowing of the aortic valves), hepatic steatosis (fatty liver disease) and liver inflammation. E06 antibody-producing mice had 32 percent less serum amyloid A, a marker of systemic inflammation.

The E06 antibody also prolonged the life of the mice. After 15 months, all of the E06 antibody-producing mice were alive, compared to 54 percent of the control mice.

“We showed for the first time that OxPL are truly pro-inflammatory and pro-atherogenic and, moreover, that they can be counteracted by E06 antibody,” Witztum said. “This suggests that therapies that inactivate OxPL may be beneficial for reducing inflammation in general, and in particular in the case of diseases such as atherosclerosis, aortic stenosis and hepatic steatosis.”

Witztum and team are now testing E06 antibody in mouse models of human diseases linked to inflammation, such as osteoporosis (bone loss) and nonalcoholic steatohepatitis (NASH, a type of liver disease).

Learn more: Antibody Blocks Inflammation, Protects Mice from Hardened Arteries and Liver Disease

 

 

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Just a single dose of Trodusquemine reverses atherosclerosis in mice

via University of Aberdeen

A new drug being trialled for treating breast cancer and diabetes has been shown to ‘melt away’ the fat inside arteries that can cause heart attacks and strokes.

Researchers from the University of Aberdeen, using pre-clinical mouse models, showed that just a single dose of the drug (Trodusquemine) completely reversed the effects of a disease that causes a host of heart problems.

Atherosclerosis is the build-up of fatty material inside the arteries.

Over time this fatty material can grow bigger until your arteries become so narrow that not enough blood can pass through.

Atherosclerosis is the condition that causes most heart attacks and strokes.

In pre-clinical tests, mice with set-in atherosclerosis, mimicking what happens in humans, had less fatty plaques in their arteries whether they had regular doses over time or just a single dose of Trodusquemine.

The drug works by stopping an enzyme called PTP1B, which is normally increased in people with obesity or diabetes and conditions involving prolonged inflammation such as sepsis, inflamed diabetic foot ulcers and allergic lung inflammation. The researchers found that it also stimulated the action of another protein (AMPK), which effectively mimics exercise and reduces chronic inflammation.

It has already been shown to be effective with diabetes and breast cancer patients but this is the first time the drug has been shown to have benefits for long-term cardiovascular disease.

The £236,000 study was funded by the British Heart Foundation.

Professor Mirela Delibegovic and Dr Dawn Thompson from the University of Aberdeen’s Institute of Medical Sciences who led the study said: “All humans have some level of atherosclerosis. As you age you start to develop these fatty streaks inside your arteries. It is a big problem for people who are overweight or have underlying cardiovascular conditions.”

“Trodusquemine has already been trialled for treatment of diabetes and breast cancer but this is the first time it has been used in models of atherosclerosis.

“These have only been tested at pre-clinical level, in mice, so far but the results were quite impressive and showed that just a single dose of this drug seemed to completely reverse the effects of arthrosclerosis.

“The next step is to test the ability of this drug to improve outcomes in human patients with developed atherosclerosis and cardiovascular disease”.

Learn more: Drug ‘melts away’ fat inside arteries

 

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Keeping Atherosclerosis in-check with Novel Targeted Inflammation-Resolving Nanomedicines

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Nanometer-sized “drones” that deliver a special type of healing molecule to fat deposits in arteries could become a new way to prevent heart attacks

Nanometer-sized “drones” that deliver a special type of healing molecule to fat deposits in arteries could become a new way to prevent heart attacks caused by atherosclerosis, according to a study in pre-clinical models by scientists at Brigham and Women’s Hospital (BWH) and Columbia University Medical Center. These findings are published in the February 18th online issue of Science Translational Medicine.

Although current treatments have reduced the number of deaths from atherosclerosis-related disease, atherosclerosis remains a dangerous health problem: Atherosclerosis of the coronary arteries is the #1 killer of women and men in the U.S., resulting in one out of every four deaths. In the study, targeted biodegradable nano ‘drones’ that delivered a special type of drug that promotes healing (‘resolution’) successfully restructured atherosclerotic plaques in mice to make them more stable. This remodeling of the plaque environment would be predicted in humans to block plaque rupture and thrombosis and thereby prevent heart attacks and strokes.

“This is the first example of a targeted nanoparticle technology that reduces atherosclerosis in an animal model,” said co-senior author Omid Farokhzad, MD, associate professor and director of the Laboratory of Nanomedicine and Biomaterials at BWH and Harvard Medical School (HMS). “Years of research and collaboration have culminated in our ability to use nanotechnology to resolve inflammation, remodel and stabilize plaques in a model of advanced atherosclerosis.”

In this study, targeted nanomedicines made from polymeric building blocks that are utilized in numerous FDA approved products to date, were nanoengineered to carry an anti-inflammatory drug payload in the form of a biomimetic peptide. Furthermore, this peptide was derived from one of the body’s own natural inflammatory-resolving proteins called Annexin A1. The way the nanomedicines were designed enabled this biological therapeutic to be released at the target site, the atherosclerotic plaque, in a controlled manner.

In mouse models with advanced atherosclerosis, researchers administered nanomedicines and relevant controls. Following five weeks of treatment with the nanomedicines, damage to the arteries was significantly repaired and plaque was stabilized.

Specifically, researchers observed a reduction of reactive oxygen species; increase in collagen, which strengthens the fibrous cap; and reduction of the plaque necrotic core, and these changes were not observed in comparison with the free peptide or empty nanoparticles.

“Many researchers are trying to develop drugs that prevent heart attacks by tamping down inflammation, but that approach has some downsides,” said co-senior author Ira Tabas, MD, Richard J. Stock professor of Medicine (Immunology) and professor of Pathology & Cell Biology at Columbia. “One is that atherosclerosis is a chronic disease, so drugs are taken for years, even decades. An anti-inflammatory drug that is distributed throughout the entire body will also impair the immune system’s ability to fight infection.” That might be acceptable for conditions that severely affect quality of life, like rheumatoid arthritis, but “using this approach to prevent a heart attack that may never happen may not be worth the risk.”

In addition, it’s not enough to deliver an anti-inflammatory drug to the plaques, said Columbia associate research scientist Gabrielle Fredman, PhD, one of the study’s lead co-authors. “Atherosclerosis is not only inflammation; there’s also damage to the arterial wall. If the damage isn’t repaired, you may not prevent heart attacks.”

The targeted nanomedicines used in this current study were engineered by researchers at BWH. Following preliminary proof-of-principle studies at Columbia University in models of inflammation, they were further tested in a clinically relevant disease model in mice and were shown to be capable of maneuvering through the blood circulation, and traversing leaky regions through to the inside of the plaques, as was demonstrated by fluorescence microscopy imaging of the plaque lesions.

Researchers note that in addition to their specific ‘sticky’ surfaces, their small sub-100 nanometer size is also a key property that facilitates the retention and accumulation of these nanoparticles within the plaques. These nanoparticles are 1000 times smaller than the tip of a single human-hair strand.

“These nanomedicines are developed using biodegradable polymers that can break-up over time in the body using the bodies natural mechanisms, and can be nanoengineered using scale-able chemistries and nanotechnologies, which ultimately can facilitate their rapid translation to the clinic,” said co-lead author Nazila Kamaly, PhD, instructor in the Laboratory of Nanomedicine and Biomaterials at BWH and HMS.

Researchers caution that although plaques in mice look a lot like human plaques, mice do not have heart attacks, so the real test of the nanoparticles will not come until they are tested in humans. “In this study, we’ve shown, for the first time, that a drug that promotes resolution of inflammation and repair is a viable option, when the drug is delivered directly to plaques via nanoparticles,” said Tabas. To be ready for testing in humans, the team plans to fine-tune the nanoparticles to optimize drug delivery and to package them with more potent resolution-inducing drugs. “We think that we can obtain even better delivery to plaques and improve healing more than with the current peptides,” , he said.

Read more: Keeping Atherosclerosis in-check with Novel Targeted Inflammation-Resolving Nanomedicines

 

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